Macromolecules termed “sulfonylurea receptors” (SUR) are found in many body tissues and are important in many physiological activities. Among many important functions, SUR are involved in insulin release from pancreatic beta cells, and may affect blood pressure by affecting vascular smooth muscle. There are multiple SUR, including a type 1 sulfonylurea receptor (SURD, a type 2 sulfonylurea receptor (SUR2) and subtypes of these receptors. Molecularly distinct SURs are coupled to distinct ion channel moieties in various tissues to form, for example, different KATP channels with distinguishable physiological and pharmacological characteristics. KATP channels in pancreatic beta cells are formed from SUR1 linked with a K+ channel, whereas the cardiac and smooth muscle KATP channels are formed from SUR2A and SUR2B, respectively, linked to K+ channels.
A newly identified calcium and adenosine triphosphate sensitive non-selective cation channel (NCca-ATP channel) is another ion channel affected by compounds that affect SUR. NCca-ATP channels are found in neural tissue and neural cells following trauma, stroke, ischemia, and other injuries and conditions (Simard et al., U.S. patent application Ser. No. 10/391,561, published as 2003/0215889; Simard et al., U.S. patent application Ser. No. 10/391,561, published as 2006/00100183).
Sulfonylurea drugs are commonly used to treat patients having blood glucose level disorders, such as patients with diabetes. Sulfonylurea drugs have other uses in addition to treating diabetes. For example, sulfonylurea drugs interact with SUR and affect the activity of ion channels found in many tissues, including neural tissue such as neurons, glial cells, and other cells in the brain, spinal cord, and peripheral nervous system. Ion channel types associated with SUR and affected by sulfonylurea (and other drugs acting on SUR) include potassium channels and non-selective channels. SUR is responsible for activation of some potassium channels by a chemically diverse group of agents termed K+ channel openers, such as diazoxide, pinacidil, and cromakalin.
Sulfonylurea drugs commonly used in clinical applications include antidiabetic sulfonylureas such as glibenclamide and tolbutamide, and may also include repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride and other drugs or metabolites of drugs which interact with SUR.
Such drugs are typically poorly water soluble, and are commonly given as pills or in other solid form. However, some patients are not able to swallow pills, or otherwise would be better served if these drugs were readily available for delivery in another form besides solid pills or powders. Oral administration of solid dosage forms typically results in a time-lag before clinically effective dose levels are reached in the patient's tissues and internal fluids, and makes maintenance of constant levels of drug in those tissues and fluids difficult. Furthermore, pH fluctuations in the stomach or gut can alter the absorption rates of drugs. Accordingly, there is need in the art for alternative formulations of drugs acting at a SUR, including alternative formulations of sulfonylurea drugs such as glibenclamide, tolbutamide, and other drugs that act on SUR.